Based on growth and aging of the U.S. population, medical expenditures for cancer in the year 2020 are projected to reach at least $158 billion. If newly developed tools for cancer diagnosis, treatment, and follow-up continue to be more expensive, medical expenditures for cancer could reach as high as $207 billion, said the researchers from the National Cancer Institute (NCI), part of the NIH (see http://www.nih.gov/news/health/jan2011/nci-12.htm).
Budget for cancer research projects of the National Cancer Institute (NCI) is in the range of USD 5 billion (see http://www.cancer.gov). A multiple of this amount is invested in cancer research worldwide by national institutes and pharmaceutical companies. The research projects funded relate primarily to the treatment of cancer, which often leads to prolonged life but not recovery.
Besides treatment, early detection of cancer is also a topic of science (see http://www.who.int/cancer/detection/en/).
Research into cancer prevention and cancer causes is primarily dedicated to the investigation of external influences to the human body, such as influences of nutrition and beverages, influence of smoking and environmental influences.
A widely neglected field remains research and investigation of prevention and causes of cancer that have no external basis, but an internal basis to which the present invention is related.
According to [1], Marie Tsampalas et al., “Human chorionic gonadotropin: A hormone with immunological and angiogenic properties”, 2010 Elsevier Ireland Ltd., the mechanisms underlying human implantation and particularly immune tolerance of pregnancy still remain to be defined in detail. HCG is the prime mediator by which the embryo announces its presence to the maternal organism since it is produced even before implantation. Among the wide range of mediators present at the implantation site, a role is becoming evident for HCG as specific blastocyst signal involved in orchestrating the implantation cascade. HCG is implicated in several actions that promote immune tolerance and angiogenesis and thus has physiological important implications for successful pregnancy. HCG is one of the earliest molecules produced by the embryo. Indeed, its mRNA is transcribed as early as the 8-cell stage and the blastocyst produces the protein before its implantation. HCG is increasingly produced after implantation by the syncitiotrophoblast. Significant levels of HCG can already be measured in the maternal blood 10 days after conception. The peak of HCG production is reached between the 10th and the 11th week of gestation, then the production decreases at the 12th week to remain at low levels for the remainder of pregnancy. HCG affects the corpus luteum to prevent luteolysis and favour stimulation of progesterone production.
HCG production is stimulated by the producing cell itself, it is known as autocrine hormone production that takes place during the above described embryonic phase. This process of autocrine hormone secretion by embryonic cells is stopped before parturition. From then on, all hormone production is controlled by brain activity. After the specified initial time period HCG is no longer produced in genetically healthy adult human cells.
By determination, the descendants of the totipotent zygote successively lose their totipotenz and follow their predetermined determination. Remarkably, each healthy cell has a cell-memory, retaining its own cell proliferation, a necessity for organized tissues, organs and stably differentiated cell types.
The presence of HCG in the human body can be measured. Pregnancy testing for example is based on the measurement of the concentration of HCG contained in the maternal urine.
HCG interacts with the Lutheneizing hormone (LH) receptor of the mother and promotes the maintenance of the corpus luteum during the beginning of pregnancy. This allows the corpus luteum to secrete the hormone progesterone, which enriches the uterus with blood vessels and capillaries so that it can sustain the growing foetus. The application of competitively binding progesterone antagonists induces an abortion, since they occupy the receptor of the progesterone controlling gene that functions to maintain pregnancy.
As described in [2], B. Maria et al., “Termination of early pregnancy by a single dose of mifepristone (RU486), a progesterone antagonist”, European Journal of Obstetrics & Gynecology and Reproductive Biology, vol. 28, no. 3, pages 249-255, (Jul. 1, 1988), the compound RU486, also known as Mifepristone, is an important progestin antagonist that effectively and safely terminates early pregnancy, when used in conjunction with a prostaglandin.
Derivatives or descendants of RU486 are described in [3], U.S. Pat. No. 6,608,074B2 and [4], U.S. Pat. No. 6,316,432B1.
As described in [5], “New Zealand Data Sheet of Mifegyne”, 3 Jul. 2013, XP855181287, Mifepristone is commercially available in tablets of 200 mg under the trade name Mifegyne®. Mifepristone is a synthetic steroid with an antiprogestational action as a result of competition with progesterone at the progesterone receptors. As further described, doses higher or equal to 1 mg/kg, mifepristone antagonises the endometrial and myometrial effects of progesterone.
[6], Wu et al: “Effects of mifepristone on the proliferation, apoptosis, and taxol sensitivity of drug-resistant human ovarian cancer cells”, 2012, XP002728256, http://en.cnki.com.cn/Article en/CJFDTOTAL-ZGAZ201202009.htm,
[7], CHELSEA R TIESZEN ET AL: “Antiprogestin mifepristone inhibits the growth of cancer cells of reproductive and non-reproductive origin regardless of progesterone receptor expression”, BMC CANCER, BIOMED CENTRAL, LONDON, vol. 11, no. 1, 27 May 2011, page 287, XP021099346, ISSN: 1471-2487, DOI: 10.1186/1471-2407-11-207, and
[8], MARISA A NAVO ET AL: “In vitro evaluation of the growth inhibition and apoptosis effect of mifepristone (RU486) in human Ishikawa and HEC1A endometrial cancer cell lines” CANCER CHEMOTHERAPY AND PHARMACOLOGY, SPRINGER, BERLIN, vol. 62, no. 3, 15 Nov. 2007, pages 483-489, XP819625528, ISSN: 1432-8843,
disclose that the growth of existing cancer cells, when exposed to Mifepristone, is reduced. Hence, mifepristone (RU486), which has been disclosed more than 30 years ago, may become an important element in cancer treatment.
In [9], EP2210585A1, compositions with an antiprogestational action are described, which have the ability to prevent the intake of the composition by the patient in an abortive amount and avoid their misuse.
As detailed above, HCG fulfils important functions in the initial phase of human life but is no longer needed at a later stage. Cells need to be able to switch genes ON and OFF individually, e.g. in order to coordinate cohabitation with neighbour cells or to ensure that hormones required for specific functions are present or not. After HCG has fulfilled its purpose, the gene responsible for HCG production is switched OFF and the related nuclear receptors are no longer activated and transcription is ceased.
Mechanisms of action of nuclear receptors are described in [10], Aranda et al., “Nuclear Hormone Receptors and Gene Expression”, PHYSIOLOGICAL REVIEWS, Vol. 81, No. 3, July 2001. For example, a lipophilic hormone may diffuse through the membrane of a cell to the cytosol. Once in the cytosol, the hormone binds to its cytosolic receptor, causing the release of an inhibitory protein from the receptor. The activated receptor then diffuses into the nucleus. In the nucleus, the receptor-hormone complex binds to the enhancer regions of hormone-regulated genes and transcription of the genes is stimulated, i.e. the gene is switched on.
While the function of HCG during the initial part of the embryonic phase is rather well known, potential effects of HCG in the post embryonic phase were not explored, as well.
In [11], M. J. Duffy and P. McGing, “Guidelines for the Use of Tumour Markers”, Scientific Committee of the Association of Clinical Biochemists in Ireland (ACBI), 3rd Edition, April 2005, HCG is known as a Tumour Marker, which occurs in elevated levels in the event that a patient suffers from malignancies such as different kind of tumours. HCG is therefore used as an indicator for a malignancy.
It seems that in extremely seldom cases, about 1 in 1027, a gene in an adult cell required for hormone production, which should be switched OFF, is accidentally switched ON and the related hormone is produced. However, this accidental status change of the cell is not without reason or cause.
It is known that a cell can adapt to external conditions. Such adaptations are typically reversible changes in the number, size, phenotype, metabolic activity, or functions of cells in response to changes in their environment. Physiologic adaptations usually represent responses of cells to normal stimulation by hormones or endogenous chemical mediators. Pathologic adaptations are responses for example to stress that allow cells to modulate their structure and function and thus escape injury. Such adaptations can take several distinct forms.
In [12], Thomas Yuill, “Cellular adaptation to toxicity”, National Library of Medicine, October 2006, it is described that adaptive changes often result in cells or organs that cannot function normally. This imperfect adaptation is a pathological change.
Hence, depending on environmental conditions and physiological and psychological influences or a mixture thereof to a human body, the cell system may be stressed and weakened and cells that suffer from pathological changes are prone to malfunction. Such an occurrence may be compared to an apparently inexplicable street accident, in which the driver has possibly actuated the accelerator pedal instead of the brake pedal. In such cases the driver has also been under the influence of psychological or environmental disturbances, which are more critical if the driver suffers from a weakness or illness at the same time. Similarly, a cell in a pathological state appears to act paradoxically at first sight. However, unfortunately, unlike the car driver, the cell will not encounter an adequate response to the malfunction but will remain under the impression that the selected state, with the undesirable gene function switched ON, is correct.
Hence, since some people will always be exposed to conditions, in which extensive cell adaptations over a longer period of time occur, e.g. by consumption of unhealthy nutrition, lack of physical exercises or disturbing influences, such as stress or unclean air, diseases will always occur that have the origin in the pathological state of cells located in a part of the human body.
In [13], Laurence A Cole, “hCG, the wonder of today's science” Reproductive Biology and Endocrinology 2012, http://www.rbej.com/content/10/1/24, it is stated that cancers start out as transformed cells driven by an HCG-independent process. Only after the cancer progresses and becomes advanced it would become able to express the HCG β-subunit gene and make HCG free β-subunit. The HCG free β-subunit driven TGFβ antagonism mechanism then would take over control of the cancer, as indicated by vaccine studies, and would reach complete control of the advanced disease.